Flaviviruses are a group of positive-stranded RNA viruses that have a global impact due to their widespread distribution and ability to cause disease in humans and economically important domesticated animals. Several members of this group, such as dengue virus (DEN) and West Nile virus (WNV), are considered emerging or re-emerging pathogens because the incidence with which they encounter humans and cause disease is increasing each year at an alarming rate. Thus, an urgent need exists for the development and implementation of safe and efficacious vaccines and therapies. The envelope proteins present on the surface of flavivirus virions are the primary targets for the humoral (antibody-mediated) immune response during natural infection. Thus, the generation of antibodies capable of binding to this array of viral proteins and blocking infection is a critical aspect of the immune response, and an important goal of vaccine development. However, under some circumstances, the presence of antibodies can also increase the efficiency of viral infection. Importantly, this antibody-dependent enhancement (ADE) of infection has been linked to a more severe clinical outcome of DEN infection (Dengue hemorrhagic fever; DHF). The possibility that immunization may elicit antibodies capable of enhancing infection poses a significant challenge for the development of a DEN vaccine, and highlights the importance of understanding not only the magnitude, but also the breadth, specificity, and persistence of humoral immunity following vaccination. In this regard, we are investigating the mechanisms of antibody-mediated neutralization and ADE with the goal of understanding the biochemical and cellular factors that determine the outcome of the interaction of flavivirus particles with antibody.